1. Field
The disclosure relates to a method for predicting patient responsiveness to Crohn's disease treatments involving antagonizing tumor necrosis factor-α (“TNF-α”), another tumor necrosis factor superfamily member, or a cytokine, and to a method of monitoring the effectiveness of such therapy. The disclosure also relates to a method for screening compounds for use in the treatment of Crohn's disease. The disclosure also relates to a method for monitoring the disease state in Crohn's disease patients.
2. Description of the Related Art
Autoimmune disease is characterized by production of either antibodies that react with host cells or immune effector T cells that are autoreactive. Autoantibodies are frequently identified in certain types of autoimmune disease, such as anti-acetylcholine receptor antibodies in myasthenia gravis and anti-DNA antibodies in systemic lupus erythematosus. However, such autoantibodies are not seen in many types of autoimmune disease. Moreover, autoantibodies are often detected among healthy individuals, but such antibodies do not induce autoimmune disease. Thus, beside autoantibodies, additional yet-to-be identified mechanisms are evidently involved in the pathogenesis of autoimmune disease.
Once autoantibodies bind to the target host cells, the complement cascade is thought to be activated to form the C5-9 membrane attack complex on the target cell membranes, which leads to the death of host cells (see Esser, Toxicology 87, 229 (1994)). By-product chemotactic factors, such as C3a, C4a, or C5a recruit more leukocytes to the lesion (see Hugli, Crit. Rev. Immunol. 1, 321 (1981)). Recruited leukocytes or naturally present leukocytes at the lesion recognize antibody-bound cells (immune complex) via Fc receptors (“FcR”). Once the FcR is cross-bridged by the immune complex, leukocytes release TNF-α (see Debets et al., J Immunol. 141, 1197 (1988)), which binds to specific receptors present on the surface of host cells, and induce apoptosis or cell damage (see Micheau et al., Cell 114, 181 (2003)). Activated FcR also initiates the release of chemotactic cytokines to recruit different subsets of leukocytes to the lesion (see Chantry et al., Eur. J. Immunol. 19, 189 (1989)). In addition to the FcR, T cell receptors (“TCR”) on cytotoxic T cells may also recognize host cells, and an activated TCR functions in the same manner as cross-bridged FcR (see Brehm et al., J. Immunol. 175, 5043 (2005)). TCR function is well characterized in terms of antigen presentation with an interaction with major histocompatibility complex (MHC) molecules (see Isaacs et al., Inflamm. Bowel Dis. 11 Suppl 1, S3 (2005), and Garcia et al., Cell 122, 333 (2005)). Although the TCR-mediated cytotoxic function is not well characterized, it may be involved in cases where no autoantibody is identified, because immunoglobulins and the TCR are unique molecules which are capable of recognizing the specific structure of the target. This is an overall hypothesis of the molecular mechanism of autoimmune disease.
Crohn's disease (“CD”) is an immune disease involving inflammation of the gastrointestinal tract. Although it is well characterized clinically, its pathogenesis is poorly understood. It is known, however, that the expression of TNF-α, also known as tumor necrosis factor superfamily member 2 (“TNFSF-2”), is increased in inflammatory bowel diseases such as CD. Although mild to moderate CD may be treated with 5-ASA agents such as sulfasalazine, glucocorticoids, or purine analogs such as azathioprine or 6-mercaptopurine, therapeutic options for severe CD cases refractory to standard therapies, such as the administration of cyclosporine, tacrolimus, or anti-inflammatory cytokines, are limited and of varying effect. Most CD patients will require at least one surgical intervention. Because the choice of therapeutic options depends on an assessment of the disease state in CD patients, it would be desirable to develop new methods of evaluating the disease state and monitoring the progression of the disease.
The development of infliximab (Remicade®), a chimeric mouse-human monoclonal antibody against TNF-α, has been a recent advance in the therapy of severe CD. However, only about 65% of patients will respond to this agent, and only about half of those patients will enter complete remission after repeated infusions of the antibody (typically, once every 8 weeks for 44 weeks). Because of the cost of the treatment, which can amount to tens of thousands of dollars per year, a method of quickly and easily assessing whether a CD patient would be a good candidate for infliximab therapy, and of assessing the effectiveness of infliximab therapy once treatment has begun, would be highly desirable. Furthermore, a method of rapidly screening new agents that could be of use in treating CD would be of great benefit in developing new therapies to complement or supplant existing therapies.